Unresectable Metastatic Testicular Germ Cell Tumor with Low-Grade Neuroglial Neoplasm, Stable After Radiation and Chemotherapy

Abstract

We present an 18-year-old male who presented with a 16 cm testicular tumor alongside multiple lesions in the lungs, right pelvis with involvement of the ischio/pubic bone, and enlarged pelvic lymph nodes on imaging, suspicious for metastatic disease. Histologic and immunohistochemical examinations revealed an embryonic type neuroectodermal tumor (somatic type malignancy, 10%) arising in a malignant mixed germ cell tumor composed of teratoma (50%), embryonal carcinoma (10%) and yolk sac tumor (30%). After treatment with chemotherapy and radiation, repeat imaging demonstrated a right pelvic sidewall mass that decreased in size from 40 mm at 11 months after the initial diagnosis, to 18 mm at 22 months after the initial diagnosis. A right pelvis medial thigh wall mass that had a lytic bone component showed a slight increase in size from 151 mm at 11 months after initial diagnosis to 154 mm at 22 months after the diagnosis. On biopsies performed at 3 months, 10 months, and 26 months after the initial diagnosis, this lytic lesion consistently demonstrated a neoplasm composed of low-grade neuroglial differentiation. This is the first case in the medical literature where residual malignant germ cell tumor consisting of low-grade neuroglial neoplasm in a site that is not amenable to resection without significant morbidity. The tumor initially regressed with traditional first-line chemo-radiotherapy regimen but regrew and stabilized with second regimen of chemotherapy. The clinical course of this case invites consideration for an active surveillance approach in cases with similar characteristics.

Background

We previously published a case series of 13 patients with testicular germ cell tumors with neuroglial neoplasms including low-grade astrocytomas, gemistocytic astrocytoma, anaplastic astrocytomas, ganglioneuroma, glioblastomas, and gliosarcoma.¹ Most of the tumors of that series were resections of retroperitoneal lymph nodes with metastases that were considered recurrences or persistent disease after chemotherapy. A smaller proportion of neuroglial neoplasms were detected in primary tumors, always associated with other malignant germ cell tumors, most frequently teratomas.^{1, 2} Neuroglial neoplasms arising in the central nervous system (CNS) are treated with resection followed by radiation and chemotherapy, mainly due to the inability to remove them completely without causing significant morbidity. The effect of chemotherapy or radiation therapy in neuroglial neoplasms arising in testicular germ cell tumors is unknown. At the time of our previous publication, none of the patients had presented unresectable neuroglial neoplasms requiring adjuvant therapy. Here, we present the first case of neuroglial neoplasm in a metastatic testicular germ cell tumor in an unresectable site, and describe its evolution after multimodal therapy.

Case Report

The patient is an 18-year-old male who presented with a testicular mass. A CT scan showed a 16 cm testicular tumor and multiple lesions suspicious for metastasis to the lungs, and right pelvis with involvement of the ischio/pubic bone, and enlarged pelvic lymph nodes (Figure 1A and 1B). Radical orchiectomy revealed a tumor showing 10% of somatic-type malignancy consisting of embryonic type neuroectodermal tumor (figure 1C and 1D), previously known as primitive neuroectodermal tumor or PNET)³ arising in a malignant mixed germ cell tumor composed of teratoma (50%), embryonal carcinoma (10%) and yolk sac tumor (30%). Serologic markers were elevated as follows: alpha fetoprotein (AFP) 920 ng/ml (normal range 0-10 ng/ml), HCG 36 IU/mL (normal range: 0-1.0 IU/mL), and lactate dehydrogenase (LDH) 920 U/L (normal range 118-273 U/L). Molecular studies detected amplification of CCND2, FGF23, FGF6, KDM5A, and KRAS. The tumor was microsatellite stable and the mutational burden was low (1 Mut/Mb).

Figure 1:

A&B: Image studies of testicular mass and pelvis at the time of diagnosis. A. CT scan shows left testicular mass (*) measuring 16 cm in largest dimension and a right pelvic mass (**). B. MRI shows right pelvic mass (*) involving ischial tuberosity and surrounding pelvic wall soft tissue. C&D: Histopathology of embryonic type neuroectodermal tumor component of the testicular mixed germ cell tumor. C. Low-power view shows a predominantly solid tumor composed of cells with primitive appearance and rosette formation. D. Higher power of “C” showing tumor cells with round to oval nuclei, inconspicuous nucleoli and scant eosinophilic cytoplasm. E&F: Histopathology of ischial tuberosity resistant to chemotherapy and prior to radiation therapy. E. Low power view shows sheets of round and spindle cells with eosinophilic fibrillary cytoplasm. Insert shows strong and diffuse GFAP staining. F. Higher-power of “E” neuroglial cells with oval shaped hyperchromatic nuclei in a neurofibrillary background. G&H: Histopathology of mass in ischial tuberosity after chemotherapy and radiation therapy. G. Low-power view shows cords of spindle cells in a fibrous background. Insert shows strong and diffuse GFAP staining. H. Higher power view of “G” showing spindle and multinucleated cells with eosinophilic cytoplasm and fibrillary background. Insert shows Ki-67 proliferation rate is low (<5%)

The patient received chemotherapy regimen consisting of four cycles of VIP (etoposide, ifosfamide, and cisplatin). Ifosfamide was included in the plan to target the embryonic type neuroectodermal tumor component of the tumor.⁴ Although there was resolution of the pulmonary lesions and normalization of tumor markers, there was still considerable tumor remaining in the ischiopubic bones and pelvic sidewall. The pelvic mass was biopsied to better define the tumor characteristics. Histologically, this mass showed infiltrating nests of tumor cells with oval hyperchromatic nuclei in a fibrillary background (Figure 1E and 1F). Immunohistochemistry stains showed diffuse strong expression of glial fibrillary protein (GFP), which along with the morphology, supported the neuroglial differentiation of the tumor. There was no morphologic evidence of a PNET component in the biopsy. Immunohistochemistry for PD-L1 was negative with a combined positive score (CPS) score of < 1. A hemipelvectomy was proposed but the patient declined it due to the potential morbidity of the procedure, and instead opted for radiation therapy. He received a total cumulative dose of 3750 cGy. Several months after completion of radiation therapy, the large irregularly shaped mass, centered in the right ischium, and involving the right acetabulum, inferior public ramus, and right pelvic sidewall, increased in size, suggestive of progressive disease. The patient then received second-line chemotherapy consisting of an irinotecan and temozolomide based regimen.

Repeat imaging studies, 15 months after initiation of second line chemotherapy, showed that the large pelvic mass centered in the right ischium was stable in size. A repeat biopsy also showed a neuroglial neoplasm that was slightly less cellular than the pre-radiotherapy sample (Figure 1G and 1H). Tumor cells showed a spectrum of morphologies including spindle, epithelioid and multinucleated cells, with eosinophilic cytoplasmic processes, and surrounded by a fibrillary background. A Ki-67 proliferation rate was low (<1%) (Figure 1H). Next generation sequencing on this sample again revealed copy number gains in KRAS and CCND2, consistent with the molecular studies from an earlier sample.

Discussion

Metastatic testicular germ cell tumor that recurs with neuroglial neoplasms are extremely rare. In a previous series that included recurrent germ cell tumor, there was only one case with neuroglial neoplasm in a series of 124 patients.⁵ The orchiectomy specimen of this patient had showed embryonic type neuroectodermal tumor without a more differentiated neuroglial component, which was only seen in the recurrence after initial chemotherapy. This has been the most common clinical scenario in previously reported cases with neuroglial neoplasm arising in germ cell tumors, where the differentiated neuroglial component is seen in the recurrence of patients with a previous embryonic type neuroectodermal tumor in the primary tumor.¹ Following our previous study on neuroglial tumors arising in germ cell tumors, the current case could be classified as a WHO grade I/II astrocytoma, given the lack of mitoses, necrosis or nuclear pleomorphism. This neuroglial component would technically be considered a somatic malignancy arising in a germ cell tumor.⁶ However, given that the oncologic and urologic communities commonly associate the term “somatic malignancy” with sarcomas or carcinomas arising in germ cell tumors, we have previously proposed to designate these neoplasms as “neuroglial neoplasm” and use the closest nomenclature that would have been used in the central nervous system.¹

We previously reported one case of a testicular tumor with a wide spectrum of a differentiated neuroglial components in which a small focus of embryonic type neuroectodermal tumor was identified, suggesting that the differentiated neuroglial neoplasms originated from it. Subsequently, Magers et al. published a series of 13 patients with concomitant embryonic type neuroectodermal tumor and differentiated neuroglial components in a retrospective review of 54 cases, which indicates that this phenomenon can be seen relatively more frequently than previously thought.⁷ In contrast to the cases presented by Magers et al.,⁷ this patient had the same low-grade neuroglial neoplasm in all three biopsies and was not an isolated focus within a tumor with other primitive or high-grade areas. Although a sampling error cannot be excluded with certainty, it is unlikely that the tumor would have shown areas of higher grade given that it was stable over the follow up time available.

It has been previously documented that metastatic embryonic type neuroectodermal tumor arising in a testicular germ cell tumor has a poor prognosis and patients relapse despite chemotherapy.⁸ To the best of our knowledge, there have not been any reports in the literature on outcome of patients with low-grade neuroglial neoplasms that were unresectable and were treated with radiation and/or chemotherapy. In our previous series, we reported a patient with metastasis from a gliosarcoma, but none of the cases showing a low-grade neuroglial neoplasm had a recurrence after excision. The traditional clinical approach in the presence of a recurrent germ cell tumor is its complete resection when possible, assuming that any residual tumor could potentially limit the patient’s survival. The clinical case presented here emphasizes that unresectable tumors with low-grade neuroglial differentiation could be managed by radiation and chemotherapy, aiming to stabilize the disease. Of note, a personalized therapeutic approach would be the standard of care in low-grade gliomas of the central nervous system, emphasizing an “onco-functional balance” approach to surgery and medical therapies.⁹ Additional cases are needed to be able to arrive at conclusions that could be generalized to other patients with similar clinical presentations; however the current case suggests that low-grade neuroglial tumor as residual malignant mixed germ cell neoplasia could be managed conservatively to avoid major surgical morbidity.